Cellular trafficking of amyloid seeds and the instigation of Alzheimer-like pathology in a transgenic mouse model The aggregation and intracerebral accumulation of beta-amyloid (A) is the earliest known biomarker of Alzheimer's disease. How the aggregation of A is initiated and the means by which the abnormal protein is subsequently dispersed remain unknown. Recent evidence has implicated macrophages in the ingestion and transport of pathogenic A 'seeds' from the periphery to the brain, and axonal transport in the directed spread of the seeds within the brain. Specifically, our preliminary data demonstrate that aggregated A injected intraperitoneally can be detected in circulating macrophages, and A injected into the dorsal hippocampus can seed A deposition selectively in the ventrolateral entorhinal cortex, a brain region that is distant from the injection site. Because the entorhinal cortex and hippocampus are highly interconnected, this finding suggests that axonal transport may be responsible for seed transport from one brain region to another, and thus may explain the systematic spread of pathology through the brain. However, there is still no direct evidence for the trafficking of A seeds by these mechanisms to and within the brain. This proposal will test the hypothesis that macrophages and neurons act as cellular Trojan horses by introducing pathogenic protein seeds into distant sites, where they mediate the subsequent emergence of lesions. Successful completion of this project will help to identify new cellular and molecular targets for therapeutic intervention in Alzheimer's disease, such as the uptake, processing, transport, or intercellular transfer of proteopathic seeds. PUBLIC HEALTH RELEVANCE: Approximately 5.4 million people in the United States suffer from Alzheimer's disease, and as the aging population increases, a monumental burden on healthcare is imminent. Alzheimer's disease is marked by profound brain changes and dementia, and currently has no effective disease-modifying treatment, despite numerous recent clinical trials of drugs targeting various mechanisms. Genetic, pathologic and biochemical evidence supports the hypothesis that the misfolding and aggregation of the protein fragment A as a critical occurrence in the development of Alzheimer's disease. This project is designed to elucidate the cellular mechanisms involved in the transport of disease-causing A seeds from one site to another. The findings will help to determine how the lesions proliferate in the brain, and thus pave the way to new therapeutics that target the causative factors of this devastating disease.